The long-term objectives are to discover and develop new drugs for the treatment of obesity in humans. In Phase I, new drug lead candidates will be found by screening selected libraries drawn form Chemical Diversity Labs' collection of 550,000 publicly available chemical compounds. Screening candidates will be selected on ADME criteria for the likelihood that they will exhibit specific inhibitory activity against mammalian acetyl CoA carboxylase 2 (ACC2). ACC2 is found in mitochondria, where it regulates fatty acid oxidation. Inactivation of ACC2 in the mouse has been shown to reduce weight gain enormously. We will develop screening strains of yeast to test for inhibition of human ACC2 by replacing the yeast ACC gene by human ACC2 cDNA. Such replacement strains carrying wheat chloroplast or toxoplasma ACC have been shown by us to be sensitive to ACC-specific chemical inhibitors. Test strains carrying the human ACC2 will be challenged with compound libraries containing a large number of compounds related in structure to the known ACC-specific herbicides. Lead candidates, identified by inhibition of growth of yeast replacement strains, will be evaluated subsequently by biochemical assays. In Phase II of the project more extensive bioassays and testing in animals will be used to select drug development lead compounds from among the Phase I lead candidates and perform initial optimization studies, leading to one or more drug candidates ready for extended animal and clinical development.